Suvorexant for the treatment of insomnia

Abstract

Suvorexant (Belsorma^®) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5–15 mg were efficient and probably safe, whereas the sponsors had proposed 15–40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant’s market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds.

Keywords::

• almorexant
• Belsorma
• drug development
• FDA
• hypocretin
• insomnia
• NDA
• orexin
• orexin receptor antagonists
• pharmacodynamics
• pharmacokinetics
• SB649868
• sleep disorders
• suvorexant

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Orexin antagonism: Orexin receptor antagonism is a new approach that has had at least four positive clinical validations/proof of concepts in Phase II/Phase III in both volunteers and primary insomniacs.

• Adverse events: The suvorexant re-filing was successful. Filorexant, a potential backup to suvorexant has been dropped from the Merck pipeline, SB649868 has been stopped, like almorexant, despite apparent success in Phase III. The reasons why the other three compounds, all dual orexin receptor antagonist (DORAs), were stopped are subject to speculation; in the case of almorexant, non-specified safety issues were mentioned.

• Pharmacokinetics: From the safety studies and/or sleep profiles of suvorexant, almorexant and SB649868, one may suggest residual next-morning effects, certainly at higher doses, since all three compounds show relatively long Tmax and half-lives; the assumption that next morning, the increase in brain orexin would stop the antagonist from producing ‘sedating’ effects may be a wishful thinking.

• Receptor kinetics: Suvorexant, almorexant, filorexant and SB649868 have very slow receptor kinetics: they seem to bind to, and dissociate from the orexin receptors very slowly. In other words, receptor occupancy/target engagement may outlast predictions from simple plasma pharmacokinetics.

• Rapid eye movement (REM) sleep, physiological sleep and restorative sleep: Suvorexant, almorexant and SB649868 are DORAs, which in rodents and humans may favor REM over slow wave sleep/non-rapid eye movement sleep, and possibly induce sleep onset REM; thus, physiological sleep may not have been achieved. More studies are needed to study the impact of DORAs on sleep architecture in humans, preferably patients.

• Receptor subtype selective compounds: There is circumstantial evidence in rodents that selective OX₂R antagonism may produce more balanced and restorative sleep. This is another avenue to explore, although by no means proven in the human situation. Proof-of-concept studies are needed.